Meloxicam by drdoc on-line 
 

Meloxicam is variably claimed by Boehringer Ingelheim to be the First Generation of Selective COX 2- Cyclooxygenase Enzyme Inhibitors.

However it is NOT a specific COX 2 drug and inhibition of COX 1 occurs at its therapeutic concentration - causing the same overall profile of side effects as seen with the other conventional non steroidal anti-inflammatory drugs (NSAIDs). Only Celecoxib and Rofecoxib can claim true specificity. Meloxicam is NOT a COXIB class drug. It is now available in the USA, but in my opinion must be seen as an old fashioned NSAID that belongs with the group of NSAIDs associated with classical COX 1 side effects of Gastropathy and effects on platelets and kidneys.

The COX1 - constitutive form performs the housekeeping functions responsible for physiological prostaglandin production especially in the Gastric, mucosa and Kidney. Inhibition of this produces side affects of Non-steroid Anti-inflammatories.
The other isoform - COX2 is induced by inflammatory mediators and has a role in inflammation. Inhibition of this is responsible for the therapeutic effects of Non-steroidal Anti-inflammatories.

Therefore, selective Non-steroidal Inhibiting COX2 - relative to COX1 theoretically retained anti-inflammatory action, but minimized the harmful side affects of those drugs. Until this time, Misoprostol in combination with anti-inflammatories has been the only recognized form of protection against gastropathy.
Large differences have been established in respect of anti-inflammatories and relative potencies against COX1 and COX2. Hence, the pharmaceutical industry searched to find a truly selective COX2 Inhibitor, whilst preserving COX1.

A symposium was held in 1995 at EULAR and that symposium is reviewed here.
The gathering is published in the Scandinavian Journal of Rheumatology - 1996, Volume 25, Supplement 102.

The symposium was introduced by Dr James Fries. -

Dr Fries in the paper titled "Toward an Understanding of NSAID Related Adverse Effects - The Contribution of Longitudinal Data Looks at the ARAMIS - Arthritis, Rheumatism and Ageing Medical Information System Statistics.". This looks at 1 700 subjects from 17 Centers in the USA. Looking at data from the general population - approximately, 3% of deaths are related to gastro-intestinal events. When looking at Rheumatoid Arthritis patients, that figure is approximately 6% - suggesting an excess death rate of approximately 3%.

The GI deaths attributable to Non-steroids represent approximately 0.1% per year.
Extrapolating such data to the USA suggests that there are 2600 gastro-intestinal mediated deaths annually caused by Non-steroidals in Rheumatoid Arthritis patients.

Risk Factors are identified - Including:
Age
Use of Prednisone
Higher anti-inflammatories doses
Disability index.

Ranking order for side affects have identified certain anti-inflammatories to be worse than others and a GI Toxicity index was also looked at.
 

In rank order:  DRUGS GI Toxicity index 
1.  Salsalate 0.871 
2. Aspirin  1.06
3.  Ibuprofen  1.16 
4.  Sulindac  1.63
5. Naproxen  1.78
6.  Piroxicam  2.07 
7. Tolmetin 2.16 
8.  Diclofenac  2.17 
9. Indomethacin  2.40
10. Fenoprofen  2.48 
11.  Ketoprofen  3.09
12.  Meclofenamate  4.03

Disease Modifying Anti-Rheumatic Drugs (DMARD), were looked at in a similar way:
 

RANK

DRUGS 

TOXICITY 

1. Hydroxychloroquine  1.38 
2.  Intra-muscular Gold 2.27 
3.  Penicillamine 3.38 
4. Methotrexate  3.82 
5. Azathioprine  3.92 
6. Auranofin  5.25

This suggests that the DMARDs are not as toxic as what was once felt and this has important implications regarding the traditional use of Non-steroidals and Disease Modifying Anti-Rheumatic Drugs in the treatment of Rheumatoid Arthritis. This would appear to justify the aggressive approach in using such DMARDs early.
John Vane and R Botting - "Mechanism of Action of Anti-inflammatory Drugs" The whole pathway of the Prostaglandin System and Cyclooxygenase is reviewed here - as is the discovery of the second Cyclooxygenase Enzyme - COX2.
In the article, he discusses the possibility of a Third Cyclooxygenase - COX3 which he considers as possibly in the brain and for which selective antagonists have yet to be found. Differences between anti-inflammatories regarding the Inhibition of COX1 and COX2 are identified.
The higher potency against COX1 than COX2 is expressed as a ratio of the IC50 Values - so that a higher COX2 to COX1 ratio indicates more potent inhibition of COX1. The IC50 represent the concentration required to produce 50% Inhibition of COX activity.
 

NSAID’s 

COX2-IC50 

COX1-IC50 

RATIOCOX2 TO COX1 

Piroxicam  0.6 0.2  0.0024 0.0006  250 
Diclofenac  1.1 0.47 1.57 0.66  0.7 
Indomethacin 1.68 0.2  0.028 0.0028 60 
Naproxen 5.65 9.57  9.56 4  0.6
Ibuprofen  72.8 25.9 4.58 0.3  15
Sulindac  112 65  1.12 0.78  100 
Aspirin 278 55  1.67 1.11  166

Of note, the lower the IC50 Value for COX1 - the less the drug concentration required to inhibit COX1 and this is seen for example., with Piroxicam - where you have a high COX2 to COX1 ratio - suggesting a very low selectivity.
Of note, is that the Diclofenac COX1 IC50 is 1.57 and the Ration is 0.7 - suggest that this is one of the more ideal existing anti-inflammatory.

The IC50 Studies are all in vitro studies and the ratios can vary according to the types of cell used and whether the tests are done instantaneously or on incubation and thus several different values for the same compound may be quoted depending of the biological system on which the tests were done.
Accurate comparisons of the selectivity of the drugs are only possible with a standard test designated for measuring inhibitory potential for the 2 isoenzymes.

In a study done by Engelhardt et al in the Journal Inflammatory Research 1995, Volume 44, Pages 422 - 433.
He does a comparative study looking at different anti-inflammatory drugs COX2 IC50 and the COX1 IC50 and Ratio of COX2 to COX1.
 

NSAIDs COX-2IC50 micromol/litre  COX1-IC50 micromol/litre  RATIOCOX2 TO COX1 
Meloxicam  0.0019 0.00577  0.33 
Diclofenac  0.0019  0.000855  2.2 
Piroxicam  0.175  0.00527 33 
Tenoxicam  0.322 0.201  15 
Indomethacin  0.00636  0.00021  30 
Tenidap  47.8  0.393  122

The source of cells were Peritoneal Macrophages from Guinea Pigs.

Clearly, the COX2 to COX1 Ratio of Diclofenac is extremely favorable. Of note, is that the COX1 IC50 for Meloxicam is 0.00577.
The application of different test systems to measure COX selectivity is a great cause of confusion and are in fact not directly comparable in different studies. So conclusion regarding the relative activity of a Non-steroidal against COX1 and COX2 are likely to be flawed if the COX2 to COX1 Ratios are obtained from different sources.
Absolute values of COX2 to COX1 Ratios from different systems should not be directly compared - however, the rank order of COX selectivity for a range of compounds, seems to be broadly reproducible from system to another.
Whilst Meloxicam may be favorably ranked regarding the COX2 Ratio, the IC50 of SC58125 was 0.09 and over a 100 micro mol for COX1 - making it 1400 more selective for COX2. Even at greater than anti-inflammatory doses, did not inhibit prostaglandin synthesis in the stomach and does not cause gastric ulceration.
SC 58635 - celecoxib (Searle) has an approximate COX2 to COX1 ratio of 325-fold.


What are my conclusions therefore:-

Clearly, the lower the IC50 for COX1, the less amount of drug required that will produce this effect. Hence, it is important to know the concentration of Meloxicam, measured in micromol, since- if this concentration is greater than the IC50 dose - then there is COX1 inhibition irrespective of the actual ratio of COX2 to COX1.
This problem is not seen with SC58125 which has a IC50 for COX1 of 100 micromol, and its COX2 to COX1 Ratio is over 1 400. The agent however is not currently being further developed.
SC 58635 - celecoxib also does not seem to show significant inhibition of COX1, and is currently in phase 3 trials, with release projected for approximately 1999.
The plasma concentrations are below the IC50 for the COX1 system, and hence - the housekeeping system remains intact.

Therefore, it is important to analyze a review of the Pharmacokinetics of Meloxicam and this is reviewed by Turck et al. from British Journal of Rheumatology - 1996, Volume 35, Supplement 1 - Pages 30 - 60. 


Meloxicam is an Enolic class NSAID drug and its tolerability is believed to be due to the preferential inhibition of COX2 over COX1.
The Pharmacokinetic characteristics of Meloxicam have been extensively investigated and Plasma concentration - Time Profiles have been obtained from more than 400 male and female volunteers in the study. The drug was administered by intravenous or Intramuscular solution as well as oral administrations.
The absorption was investigated and Plasma concentration - Time Profiles at steady state are illustrated in the Paper. The absorption of Meloxicam is independent of dose over the range 7.5 to 30mg leading to dose linear increases in Meloxicam - Plasma concentrations.
Most of the drug is bound to Albumin - greater than 99% and there is a restricted volume of distribution - it is predominantly distributed to higher perfused compartments - such as the blood, liver and kidney’s. It rapidly penetrates other tissues. 40 - 45% of the accompanying steady state Meloxicam Plasma Concentrations are found in Synovial fluid. It is eliminated by Metabolic Degradation with equal renal and faecal elimination and has a half life of 20 hours. Steady state concentrations are achieved within 3 - 5 days.
The Plasma C-max (Maximal plasma concentrations) after multiple doses range from 0.88 - 1.05mg/litre at 7.5mg and from 1.92 to 2.45mg/litre for 15mg doses. Since the molecular weight of Meloxicam is 351g/mol - the Plasma concentration after Meloxicam 7.5mg can be calculated from C-max 0.88 using a molecular weight of 351g/mol to represent 2.51 micromol- which is well above the IC50 for COX1 - making the Ratio actually irrelevant here. At C-max 1.05mg/litre using molecular weight of 351g/mol - the Plasma concentration is 2.10 micromol. At 15mg dose C-max is 1.92 mg/litre representing a concentration of 5.47micromol and the maximal C-max of 2.45 at 15mg dosing is 6.98 micromol. 

Therefore, at standard Meloxicam dosing of 7.5mg to 15mg. The concentration of drug in the Plasma far exceeds the IC50 levels that therefore, suggest that COX1 inhibition will take place. This makes the claim of being a true COX2 selective inhibitor to be potentially untrue.
It has come to my notice that the claim of COX2 selectivity has been challenged in various European Centers and that in Sweden, the claim of selectivity has been disputed and permission for registration as such has been questioned. 

In conclusion, true COX2 Selectivity - COX 2 specificity - remains valid only for 2 drugs available - Celecoxib and Rofecoxib. (Celebrex and Vioxx).

My feeling is that Meloxicam has only slightly improved COX 2 Ratios compared to Diclofenac and that its protective factor regarding gastropathy reflects this, but it is by no means a truly COX2 Selective Inhibitor (in my own personal opinion).
Diclofenac is an anti-inflammatory with similar COX1/2 ratios and provides a reasonable rank order profile.
Misoprostol remains the only registered indication for prevention of gastropathy.
Combination with misoprostol reduces ulcers and gastropathy by a further 60 %.
Numerous studies exist to confirm this - with reduction compared to Diclofenac (already relatively favorable COX2 Ratio) from 11.1% to 4.4% when compared as a study of Diclofenac versus arthrotec (Diclofenac-Misoprostol combination) 

 

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Dr David Gotlieb
drdoc on-line
Cape Town
South Africa


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